A basic understanding of the pathogenesis and immunity in mouse typhoid has now been attained. It offers a unique experimental model to study the difference in pathologic reactions resistant A/J and CBA, the susceptible C57BL/6J and BALB/c, and the congenic BALB/c Ity mice are challenged with a minimal infective dose of virulent Salmonella typhimurium. Their early tissue response to the infectious process is systematically analyzed in order to discern the basic mechanisms which render these animals different on the basis of their genetic diversity. Histopathologic development of the disease is a helpful guide to observe host response. The pathogen appears to enter blood circulation rapidly from the site of inoculation. But its subsequent growth is better contained in the organs of reticuloendothelial system of the resistant than of the susceptible host. Contrary to traditional belief, virulent Salmonella is predominantly killed within inflammatory polymorphs and macrophages. Thus, an accelerated inflammatory response and/or a more efficient ingestive activity by phagocytes in the resistant host will likely contribute to a more effective host response by localizing the pathogen at the early stage of the infection. The activation of inflammatory reaction is assessed by the total and differential populations of inflammatory cells at the site of infection (e.g., the peritoneal cavity) and by the serum amyloid P-component (SAP), and by the activation of C and C3 both systemically and locally. The relative phagocytic activity of inflammatory cells is determined by the uptake of live salmonellae in cell culture. Titration of cytokines (IFN-gamma, IL- 1 and TNF-alpha) will identify their release and mediating functions at the site of early infection. Whether these molecular mediators of tissue reactions are regulated by the Ity gene is to be defined. Such an integrated approach in the investigation of an experimental model is intended to elucidate the fundamental knowledge of host response to bacterial infections based on its genetic predispositions. A long-term objective is to understand the basic mechanisms of host resistance, through which treatments of diseases may accomplished by their modification with pharmaceutical agents.